CN101677952B - Improved depot formulations - Google Patents
- ️Wed Dec 05 2012
CN101677952B - Improved depot formulations - Google Patents
Improved depot formulations Download PDFInfo
-
Publication number
- CN101677952B CN101677952B CN2008800208290A CN200880020829A CN101677952B CN 101677952 B CN101677952 B CN 101677952B CN 2008800208290 A CN2008800208290 A CN 2008800208290A CN 200880020829 A CN200880020829 A CN 200880020829A CN 101677952 B CN101677952 B CN 101677952B Authority
- CN
- China Prior art keywords
- preparation
- polymer
- straight chain
- solvent
- lactide Prior art date
- 2007-05-18 Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polyesters Or Polycarbonates (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Biological Depolymerization Polymers (AREA)
Abstract
Disclosed are formulations and related methods that comprise a non-polymeric, non-water soluble high viscosity liquid carrier material having a viscosity of at least 5,000 cP at 37 DEG C. that does not crystallize neat under ambient or physiological conditions; a specified linear polymer comprising lactide repeat units; and one or more solvents that have a solvent capacity.
Description
Background of invention
Invention field
The present invention relates to comprise the preparation of non-polymerization, water-fast high viscosity liquid carrier material, straight chain polymer and one or more solvents.More specifically, the present invention relates to such preparation and the purposes in bioactive substance is sent thereof.
Association area is described
Extensive studies has been carried out in the biodegradable control delivery field of bioactive compound.It is useful being used for the biodegradable matrices that medicine sends, because it need not to remove the device of drug depletion.
Modal drug delivery matrix material is a polymer.Since people such as Kulkarni in 1966 reported polylactic acid synthetic and biodegradability (" the Polylactic acid for surgical implants polylactic acid of implantation (be used to perform the operation); " Arch.Surg.; 93:839), the Biodegradable polymeric field is fast-developing.The instance of having reported as other polymer of delivery apparatus host material comprises polyanhydride, such as the polyester of polyglycolic acid and lactide-glycolide copolymer, such as PEO, polyamide, polyurethanes, poe, polyacrylonitrile and the polyphosphazene of the polymer of the polyamino acid of polylysine, PEO and copolymer, end acrylic.Referring to the 4th, 891, No. 225 and the 4th of for example Langer; 906; The 4th of people such as the 4th, 767, No. 628 United States Patent (USP)s (polylactide, lactide-glycolide copolymer) of No. 474 United States Patent (USP)s (polyanhydride), Hutchinson and Tice; 530, No. 840 United States Patent (USP)s (polylactide, polyglycolic acid and copolymer).
The degradation material of biogenetic derivation is well-known, for example cross-linked gelatin.Hyaluronic acid has been crosslinked and as the degradable swollen polymer of biomedical applications (the 4th, 957, No. 744 United States Patent (USP)s of people such as Della Valle; (1991) " Surface modification of polymeric biomaterials for reduced thrombogenicity (surface modification of the polymeric biological material that blood coagulation activity reduces), " Polym.Mater.Sci.Eng., 62:731-735).
Also having developed biodegradable hydrogel is used for sending the carrier that is used as such as the bioactive substance of hormone, enzyme, antibiotic, antitumor agent and cell suspending liquid in controlled drug.Short-term preservation and this material of having realized the functional attributes of the material that quilt is carried get into local organization or body circulation controlled release.The 5th, 149, No. 543 United States Patent (USP)s referring to for example Cohen.Suitably select the hydrogel macromonomer can prepare the film that is applicable to that various surgeries, medical diagnosis and treatment are used with a series of permeabilitys, aperture and degradation rate.
Just using at present or developing many as material, especially bioactive compounds, the dispersion of carrier.Can the dispersion that be used for pharmaceutical preparation and cosmetic formulations be included into suspension or emulsion.It is the solid particle of several nanometers to hundreds of micron that suspension is defined as the particle diameter that utilizes suspending agent to be scattered in the liquid medium.This solid particle comprises microsphere, microcapsule and nanometer spheroid.Emulsion is defined as the suspension of a kind of liquid in another kind of liquid, and it is stablized through the interfacial film such as the emulsifying agent of surfactant and lipid.Emulsion preparation comprises water-in-oil emulsion and oil-in-water emulsion, multiple-phase emulsion, micro emulsion, microdroplet and liposome.Microdroplet is to have the monolayer phospholipid vesicle that the spherical lipid layer of oil phase constitutes by inside, as licenses to the 4th, 622, No. 219 and the 4th, 725, No. 442 defined that kind of United States Patent (USP) of Haynes.Liposome is through the phospholipid vesicle with water-fast polar lipid and aqueous solution preparation.Insoluble lipid has been blended in the disadvantageous entropy production that causes in the water and contained the concentric closed immobilized artificial membrane that the high-sequential of the aqueous solution of bringing into is arranged.
The 4th of people such as Dunn; 938; No. 763 United States Patent (USP)s disclose through non-reacted, water-fast thermoplastic polymer being dissolved in the biocompatible water-soluble solvent forming liquid, and this liquid is placed in the body and this solvent is dissipated to produce the method that forms implant on the spot of solid implant.Can this polymer solution be placed in the body through syringe.This implant can demonstrate its shape of cavity on every side.In optional embodiment, by the oligomeric polymer formation implant of reactive fluid, this polymer does not contain solvent and it in position solidifies to form solid through adding curing catalysts usually.
The 5th of people such as Tipton; 747; No. 058 United States Patent (USP) discloses the compositions that is used for the material controlled release, and it comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline liquid carrier materials (HVLCM) under environment or physiological condition; And (ii) by substance for delivery.
Though estimated the purposes of many materials in the material controlled delivery, the hypotoxicity preparation and the method for the controlled delivery of bioactive substance still need be provided.
Summary of the invention
On the one hand, the present invention relates to preparation, it comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition; The straight chain polymer that (ii) comprises the lactide repetitive, the lactide repetitive is R with the ratio of whole repetitives in the wherein said straight chain polymer; And one or more solvents that (iii) have solvability; The weight average molecular weight of wherein said straight chain polymer is less than or equal to about 15,000 dalton, and wherein (a) R satisfies following condition: about 0.55≤R≤about 0.95; (b) satisfy following condition as R: during about 0.55≤R≤0.85, the solvability of said one or more solvents is more than or equal to about 20%; And (c) satisfy following condition as R: greater than about 0.85 to about 0.95 the time, the solvability of said one or more solvents is more than or equal to about 10%.
On the other hand, the present invention relates to preparation, it comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition; The straight chain polymer that (ii) comprises the lactide repetitive, the lactide repetitive is R with the ratio of whole repetitives in the wherein said straight chain polymer; And one or more solvents that (iii) have solvability; The weight average molecular weight of wherein said straight chain polymer is less than or equal to about 15,000 dalton, and wherein (a) R satisfies following condition: about 0.55≤R≤0.85; And (b) solvability of said one or more solvents more than or equal to about 20%.
On the other hand, the present invention relates to preparation, it comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition; The straight chain polymer that (ii) comprises the lactide repetitive, the lactide repetitive is R with the ratio of whole repetitives in the wherein said straight chain polymer; And one or more solvents that (iii) have solvability; Wherein the weight average molecular weight of this straight chain polymer is less than or equal to about 15,000 dalton, and wherein (a) R satisfies following condition: greater than about 0.85 to about 0.95; And (b) solvability of said one or more solvents more than or equal to about 10%.
On the other hand, the present invention relates to preparation, it comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition; The straight chain polymer that (ii) comprises the lactide repetitive, the lactide repetitive is R with the ratio of whole repetitives in the wherein said straight chain polymer, wherein R satisfies following condition: about 0.55≤R≤about 0.95; And (iii) based on the total formulation weight amount, about 1% weight ratio is to one or more solvents up to about 35% weight ratio; The weight average molecular weight of wherein said straight chain polymer is less than or equal to about 15; 000 dalton, and wherein said one or more solvents comprise the combination of ethanol, ethyl lactate, Allyl carbonate, Tetrahydrofurfuryl polyethylene glycol ether (glycofurol), N-Methyl pyrrolidone, 2-Pyrrolidone, benzyl benzoate, miglyol, propylene glycol, acetone, methyl acetate, ethyl acetate, butanone, benzylalcohol, glyceryl triacetate, dimethyl formamide, dimethyl sulfoxine, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid and/or 1-dodecyl-aza-cycloheptane alkane-2-ketone and above any solvent.
Detailed Description Of The Invention
Before describing the present invention in detail, should be appreciated that the present invention does not receive the concrete exemplary materials or the restriction of method parameter, because these materials or method parameter can change certainly.It is also understood that term used herein only is intended to describe specific embodiments of the present invention, rather than restriction the present invention.
No matter all publications, patent and patent application that this paper quotes at preceding text or hereinafter, are all incorporated this paper in this integral body and are used for various purposes.
Only if context indicates clearly in addition, otherwise used singulative " a ", " an " and " the " comprises plural in this description and the appending claims.For example; " polymer (a polymer) " that mentions comprises the mixture of two kinds or more kinds of such molecule; " solvent (a solvent) " that mentions comprises the mixture of two kinds or more kinds of such compositions, and " binding agent (an adhesive) " that mentions comprises two kinds or more kinds of such mixtures of material etc.
A. introduce
The inventor unexpectedly finds; Can solve the problem of this area through preparation is provided; Said preparation comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition; The straight chain polymer that (ii) comprises the lactide repetitive, the lactide repetitive is R with the ratio of whole repetitives in the wherein said straight chain polymer; And one or more solvents that (iii) have solvability; The weight average molecular weight of wherein said straight chain polymer is less than or equal to about 15,000 dalton, and wherein (a) R satisfies following condition: about 0.55≤R≤about 0.95; (b) satisfy following condition as R: during about 0.55≤R≤0.85, the solvability of said one or more solvents is more than or equal to about 20%; And (c) satisfy following condition as R: greater than about 0.85 to about 0.95 the time, the solvability of said one or more solvents is more than or equal to about 10%.
The inventor also unexpectedly finds; Can solve the problem of this area through preparation is provided; Said preparation comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition; The straight chain polymer that (ii) comprises the lactide repetitive, the lactide repetitive is R with the ratio of whole repetitives in the wherein said straight chain polymer; And one or more solvents that (iii) have solvability; The weight average molecular weight of wherein said straight chain polymer is less than or equal to about 15,000 dalton, and wherein (a) R satisfies following condition: about 0.55≤R≤0.85; And (b) solvability of said one or more solvents more than or equal to about 20%.
The inventor also unexpectedly finds; Can solve the problem of this area through preparation is provided; Said preparation comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition; The straight chain polymer that (ii) comprises the lactide repetitive, the lactide repetitive is R with the ratio of whole repetitives in the wherein said straight chain polymer; And one or more solvents that (iii) have solvability; The weight average molecular weight of wherein said straight chain polymer is less than or equal to about 15,000 dalton, and wherein (a) R satisfies following condition: greater than about 0.85 to about 0.95; And (b) solvability of said one or more solvents more than or equal to about 10%.
In addition; The inventor unexpectedly finds; Can be through the problem that provides preparation to solve this area, said preparation comprises (i) non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition; The straight chain polymer that (ii) comprises the lactide repetitive, the lactide repetitive is R with the ratio of whole repetitives in the wherein said straight chain polymer, wherein R satisfies following condition: about 0.55≤R≤about 0.95; And (iii) based on the total formulation weight amount, with about 1% weight ratio to one or more solvents that exist up to the amount of about 35% weight ratio; The weight average molecular weight of wherein said straight chain polymer is less than or equal to about 15; 000 dalton, and wherein said one or more solvents comprise the combination of ethanol, ethyl lactate, Allyl carbonate, Tetrahydrofurfuryl polyethylene glycol ether, N-Methyl pyrrolidone, 2-Pyrrolidone, benzyl benzoate, miglyol, propylene glycol, acetone, methyl acetate, ethyl acetate, butanone, benzylalcohol, glyceryl triacetate, dimethyl formamide, dimethyl sulfoxine, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid and/or 1-dodecyl-aza-cycloheptane alkane-2-ketone and above any solvent.
Can be used to change the release spectrum of bioactive substance to be sent according to straight chain polymer of the present invention, to increase the integrity of preparation, the performance of perhaps additionally modifying preparation.Such straight chain polymer according to the present invention comprises the lactide repetitive.The instance of such polymer is lactide-glycolide copolymer.The lactide repetitive is shown in " the R row " of table 1 with the ratio R of whole repetitives in the straight chain polymer.
Important consideration is polymer and compatibility or the dissolubility of HVLCM in the preparation in the exploitation of preparation of the present invention.Polymer in preparation is not miscible or be insoluble under the situation of HVLCM with HVLCM, and being separated of polymer and HVLCM can be taken place.In case this situation takes place, possibly be difficult to polymer and HVLCM remix, particularly when soon using.If inadequately with the preparation remix, it maybe not can discharge medicine with the mode of expecting.In addition, possibly be difficult to give said preparation.Therefore, polymer and the HVLCM of expectation in the preparation is highly miscible or be dissolved in HVLCM.
Straight chain polymer in the preparation of the present invention has high compatibility or highly dissoluble in containing the preparation of HVLCM.As look-up table 1 can be learnt, the not all preparation that contains straight chain polymer, HVLCM and solvent all obtained useful preparation.The preparation of listing as " control formulation " is in context of the present invention, not to be considered to useful examples of formulations.By contrast, be useful such as those embodiment of the present invention of example in the table 1, and seldom occur being separated.
The preparation 6 that reveals acceptable solubility behavior through for example test chart can be learnt the influence of solvability.The R of NMP and 20wt% that this preparation comprises Sucrose acetoisobutyrate (SAIB), the 25wt% of 55wt% be 0.65 and Mw be lactide-glycolide copolymer (PLGA) of 5300.The solvability of preparation 6 is 25wt%.As relatively, formulation C 11 and C12 are proposed also.The R of DMSO and 20wt% that formulation C 11 comprises NMP, the 5wt% of Sucrose acetoisobutyrate (SAIB), the 20wt% of 55wt% be 0.65 and Mw be lactide-glycolide copolymer (PLGA) of 5300.Likewise, formulation C 12 comprise the R of benzyl benzoate and 20wt% of NMP, the 5wt% of Sucrose acetoisobutyrate (SAIB), the 20wt% of 55wt% be 0.65 and Mw be lactide-glycolide copolymer (PLGA) of 5300.It is good inadequately that formulation C 11 and C12 comprise less than NMP and its solvent nature aspect of 25wt%.Therefore, formulation C 11 does not satisfy the requirement of solvability with C12 and is not creative embodiment of the present invention therefore.
Embodiment 7 and 8 shows the another kind of mode of understanding solvability.These embodiments illustrate the solvability that how can measure preparation of the present invention.Except baseline nmp solvent system, in two kinds of different embodiments of two kinds of other dicyandiamide solutions and preparation of the present invention, carry out this mensuration.
Embodiment 9 and 10 illustrates the embodiment of the preparation of the present invention that comprises bioactive substance.
Now the present invention will be described in more detail.
Definition
Only if point out in addition, all percentage ratio is percentage by weight.
All lists of references that this paper quotes are incorporated into this paper as a reference in full; And be used for all purposes with same degree; As indicate publication that each is independent or patent or patent application specifically and individually by reference integral body incorporate this paper into, to be used for all purposes and/or fully to reproduce in this article.The discussion of this paper list of references only is intended to summarize these authors' opinion, is not to admit that any list of references constitutes prior art.The applicant keeps the accuracy of the list of references that query quotes and the right of dependency.
Through provide with reference to this paper as give a definition, accompanying drawing and exemplary disclosure understand the present invention best.
" give (administering) " or " giving (administration) " means with the useful mode of pharmacy and to individuality medicine be provided.
" bioactive substance " means and comprises following molecule: medicine, peptide, albumen, carbohydrate (comprising monosaccharide, oligosaccharide and polysaccharide), nucleoprotein, mucin, lipoprotein, synthetic polypeptide or albumen or the micromolecule that is connected with albumen, glycoprotein, steroid, nucleic acid (any type of DNA; Comprise cDNA or RNA or its fragment), nucleotide, nucleoside, oligonucleotide (comprising antisense oligonucleotide), gene, lipid, hormone, mineral supplements, comprise the vitamin of vitamin C and vitamin E; Or above combination in any; When giving animal in vivo; It produces biological action, and said animal includes but not limited to birds and the mammal that comprises the people.
Medicine means as the medicine of processing, treatment or prevent disease or disease at the inner or outside any material that uses, and include but not limited to immunosuppressant, antioxidant, anesthetis, chemotherapeutics, steroid (comprising retinoid), hormone, antibiotic, antiviral agent, antifungal, antiproliferative (antiproliferative), hydryllin, anticoagulant, anti-light aging agent, to melanocyte peptide (melanotropic peptide), on-steroidal and steroid anti-inflammatory compound, psychosis and the radiation adsorber that comprises the UV absorbent.
The term bioactive substance also comprises the reagent such as insecticide, pesticide, antifungal, rat poison and plant nutrient and growth promoter.
In one embodiment, preparation is vaccine and treats that substance for delivery is an antigen.Said antigen can derive from cell, antibacterial or virion or its part.As this paper definition, antigen can be albumen, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid or its combination, and said antigen causes immunogenic response in the animal such as mammal, bird or fish.As this paper definition, said immunogenic response can be body fluid mediation or cell-mediated.Under the bad situation of the antigenicity of the material that immunogenic response was directed against, can utilize such as the technology of a kind of standard covalent bond in several kinds of commercially available test kits, with this material with close such as albuminous carrier or hapten yoke.
The instance of preferred antigens comprises such as influenza proteins, human immunodeficiency virus's (HIV) albumen and first, second or the proteic virus protein of hepatitis C and bacterioprotein, such as lipopolysaccharide and gonorrhea diplococcus (Neisseria gonorrhea) albumen and the parvovirus of gram-negative bacteria cell wall.
The limiting examples of pharmaceutical substances comprises the anti-infective such as nitrofural, sodium propionate; The antibiotic that comprises penicillin, tetracycline, oxytetracycline, chlortetracycline, bacitracin, nystatin, streptomycin, neomycin, polymyxin, Gramicidin, chloromycetin, erythromycin and azithromycin; The sulfanilamide that comprises sulfacetamide, VCS-438, sulfadimidine, sulfadiazine, sulfamerazine and sulfafurazole; And the antiviral agent that comprises idoxuridine; Agaist allergic symptoms medicine such as antazoline, sleepwell (methapyritene), chlorphenamine, pyrilamine, pheniramine, hydrocortisone, cortisone, acetic acid hydrocortisone, dexamethasone, 21-dexamethasone phosphate, fluocinolone, omcilon, medroxyprogesterone, prednisolone, prednisolone 21-sodium succinate and prednisone acetate dragon; Such as ragweed pollen antigen, pollinosis pollen antigen, dust antigen and the antigenic desensitizer of milk; Vaccine such as variola, yellow fever, distemper, swine fever, chickenpox, venom, scarlet fever, diphtheria toxoid (dyptheria toxoid), tetanus toxoid, pigeon variola, pertussis, influenza, rabies, mumps, measles, poliomyelitis and Newcastle; Decongestant such as phyenlephrinium, naphazoline and tetrahydrozoline (tetrahydrazoline); Miotic and anticholinesterase such as pilocarpine, salicylic acid esperin (esperine salicylate), carbachol, diisopropyl fluorophosphate, ecostigmine and demecarium bromide; Parasympatholytic such as atropine sulfate, cyclopentolate, melyltropeine, scopolamine, tropicamide, eucatropine and hydroxyamphetamine; Such as adrenergic sympathomimetic; Tranquilizer and hypnotic such as pentobarbital sodium, phenobarbital, barbose, codeine, alpha-brominated isovalerylurea, carbromal; Antidepressant such as 3-(2-aminopropyl) heteroauxing and 3-(the amino butyl of 2-) heteroauxing; Tranquilizer such as reserpine, chlorpromazine (chlorpromayline) and acetyl piperazine coffee sodium piperazine; Such as the male steroid of methyltestosterone and fluoxymesterone (fluorymesterone), such as the estrogen of estrone, 17-, ethinyl estradiol and diethylstilbestrol, such as the pregnant preceding agent of progesterone, megestrol, melengestrol, chlormadinone, ethisterone, norethynodrel, 19-norprogesterone, norethindrone, medroxyprogesterone and 17-β-hydroxyprogesterone; For example such as the body fluid reagent (humoral agent) of the prostaglandin of PGE.sub.1, PGE.sub.2 and PGF.sub.2; Such as the antipyretic of aspirin, sodium salicylate and salicylamide, such as the spasmolytic of atropine, methantheline, papaverine and methscopolamine bromide, such as the anti-malarial agents of 4-quinolin-2-ylamine, 8-quinolin-2-ylamine, chloroquine and Pyrimethamine; Such as the hydryllin of diphenhydramine, dimenhydrinate, tripelennamine, perphenazine and chlorphenamine (chlorphenazine), such as the heart medicament of hexichol hydroflumethiazide (dibenzhydroflume thiazide), flumethiazide, chlorothiazide and aminotrate; Psychosis, it comprises typical case and atypical antipsychotic agents, wherein atypical antipsychotic agents comprises Risperidone, Paliperidone or olanzapine; Such as vitamin, natural and synthetic biologically active peptide and proteic nutrient, it comprises somatomedin, CAF, cytokine and biological respinse modifier; And acceptable salt of the medicine of above reagent and polymorph.
The amount that is contained in the bioactive substance in the compositions is enough to send the effective dose of realizing desired effects to host animal or plant.The amount that is contained in the bioactive substance in the compositions depends on the concentration of the bioactive substance that the release spectrum of expectation, biology effect are required and the expectational cycle that biological active agents discharges.
The concentration of bioactive substance also will depend on absorption, inactivation and discharge rate and the other factors well known by persons skilled in the art of bioactive substance in the compositions.Should be pointed out that dose value also will change with the seriousness of morbid state to be improved.It should also be understood that; For any concrete individuality; Should give the people's of preparation of the present invention professional judgement according to the needs of individuality and management or supervision; Adjust concrete dosage in time, and concentration range as herein described only is exemplary, is not intended the scope of invention or the enforcement of requirement for restriction protection.Can give preparation with single dose, perhaps can preparation be divided into the many smaller doses with the interval administration that changes.
Be present in bioactive substance in the preparation be generally the total formulation weight amount about 0.5% to about 30% weight ratio, and be more typically about 1% to about 20% weight ratio.Another preferable range is about 2% to about 10% weight ratio.For the very activated bioactive substance such as somatomedin, preferable range is less than 1% weight ratio, and less than 0.0001%.
" preparation " means the pharmaceutical composition that is used for embodiment of the present invention.
The molecule that " straight chain " means in the polymer forms the long-chain that does not have side chain or cross-linked structure basically.
" non-polymerization, water insoluble, 37 ℃ of following viscosity are at least 5,000cP, inhomogeneous crystalline high viscosity liquid carrier material under environment or physiological condition " means high viscosity liquid carrier material (" HVLCM "), and it is non-polymerization, water-fast; And the viscosity under its 37 ℃ is at least 5,000cP, preferably at least 10; 000cP, 15,000cP, 20,000cP, 25; 000cP or even 50,000cP, it is inhomogeneous crystallization under environment or physiological condition.Term is water insoluble be meant material under the environmental condition in water dissolved degree less than 1% weight ratio.
In preferred embodiments, when HVLCM and solvent can be with the blended low viscosity liquid carrier materials of the substrate that is used for controlled delivery (" LVLCM ") to form, the viscosity of HVLCM significantly reduced.The LVLCM/ base composition places in the body than HVLCM/ base composition usually more easily, because it flows into more easily and flows out syringe or other implanting device, and can easily be prepared into emulsion.LVLCM can have any desired viscosity.Have been found that range of viscosities also more specifically is generally used for using in the body less than the LVLCM of 1000cP less than about 2000cP.
In preferred embodiments, Sucrose acetoisobutyrate (" SAIB ") is used as HVLCM, nominally said Sucrose acetoisobutyrate is preferably by the sucrose molecule of 2 acetic acid and 6 isopropylformic acid. partial esterifications.
SAIB does not have oral toxicity and in food industry, is used for stable emulsion at present.It is for very sticking liquid and have uncommon attribute, i.e. heating or when adding solvent a little, its viscosity generation obvious variation.It dissolves in many biocompatible solvents.When in solution or emulsion, can use SAIB through injection or aerosol spray.SAIB and cellulose esters can influence the polymer-compatible of material delivery rate with other.
In other embodiments, HVLCM can be a stearate, for example those stearates of propylene glycol, glyceryl, diethylamino ethyl and ethylene glycol; Stearic amide and other long chain fatty acids amides, N for example, N '-ethylenebisstearamide, stearmide MEA and DEA, ethylenebisstearamide, coco amine oxide; Long-chain fatty alcohol, for example hexadecanol and octadecanol; Long-chain ester, for example myristyl myristate, tadenan eruciate (beheny erucate) and glycerophosphate.In one specific embodiment, HVLCM is acetylizad sucrose distearate (Crodesta A-10).The open US2004/0101557 of people's such as Gibson U.S. Patent application discloses other material that is suitable as HVLCM.
The amount of HVLCM will depend on the expectation attribute of preparation and the solvability of selected solvent in the preparation.If the solvability poor performance of selected solvent, then the actual amount of solvent can be very big, and the amount of HVLCM then correspondingly reduces in the preparation.With respect to the gross weight of compositions, the amount of HVLCM in the controlled delivery compositions is generally about 99.5% to about 10% weight ratio, and more generally 95% to 25%, and the most common 85% to 45%.
" polymer " means natural existence or the synthetic chemical compound of being made up of the series of repeat units that connects.Polymer includes but not limited to thermoplastic polymer and thermosetting polymer.Polymer can comprise straight chain polymer and/or branch polymer.Polymer can be synthesized by the monomer of single kind or can be by surpassing the synthetic copolymer of a kind of monomer.In embodiments, polymer according to the present invention comprises the polymer that comprises the lactide repetitive.Can also comprise the repetitive of other suitable material according to polymer of the present invention, it includes but not limited to Acetic acid, hydroxy-, bimol. cyclic ester repetitive, Polyethylene Glycol repetitive, caprolactone repetitive, valerolactone repetitive etc.The initiator of these polymer includes but not limited to comprise 1,6-hexanediol, 1,2-propylene glycol, 1; Ammediol, 1; The glycol initiator of 4-butanediol etc., what comprise difunctional gathers (ethylene glycol) glycol initiator (PEG), comprises the pure initiator of the simple function group of 1-dodecanol, methyl lactate, ethyl lactate etc.; The PEG that comprises methoxyl group (Polyethylene Glycol) simple function group (mPEG), and other initiator that comprises water, glycolic, lactic acid, citric acid etc.In preferred embodiments, polymer comprises Biodegradable polymeric.In other preferred embodiment, polymer comprises biocompatible polymer.In embodiments, the amount of polymer for about 1wt% to about 45wt%, the more preferably about 5wt% of the amount of polymer is about 35wt% extremely, the more preferably about 5wt% of the amount of polymer is about 25wt% extremely, all weight ratios are all based on the gross weight of preparation.In other embodiments, the amount of polymer can for about 15wt% to about 45wt%, the amount of polymer is preferably extremely about 35wt% of about 15wt%, all weight ratios are based on the gross weight of preparation.
" repetitive " means covalently bound monomer residue of going into polymer.In embodiments, the lactide repetitive comprises the lactide residue.In certain embodiments, the Acetic acid, hydroxy-, bimol. cyclic ester repetitive comprises the Acetic acid, hydroxy-, bimol. cyclic ester residue.In embodiments, straight chain polymer can have the ratio R of whole repetitives in lactide repetitive and the straight chain polymer, and wherein R can be about 0.55 to about 0.95.The scope of the R of special concern is about 0.55 to 0.85, and greater than 0.85 to about 0.95.Can confirm R via test or analysis through proton N MR or similar techniques.
" solvent " means the material that can dissolve other material.Preferably, the solvent that is used for embodiment of the present invention is a bio-compatible, miscible and/or water-soluble and/or nontoxic with water.In embodiments, bioactive substance dissolves in the solvent.Be used for solvent to mammal injection preparation of the present invention and be not taken in implantation site and produce tangible tissue stimulation or necrosis, only if stimulate or necrosis is a desired effects.
Solvent is preferably miscible and/or water-soluble with water, makes this solvent will diffuse to body fluid or other aqueous environments, thereby makes preparation demonstrate more tacky form.Miscible and/or water-immiscible solvent can not be used for embodiment of the present invention with water for some.The instance of suitable solvent includes but not limited to the combination of ethanol, ethyl lactate, Allyl carbonate, Tetrahydrofurfuryl polyethylene glycol ether, N-Methyl pyrrolidone, 2-Pyrrolidone, benzyl benzoate, miglyol, propylene glycol, acetone, methyl acetate, ethyl acetate, butanone, benzylalcohol, glyceryl triacetate, dimethyl formamide, dimethyl sulfoxine, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid and/or 1-dodecyl-aza-cycloheptane alkane-2-ketone and above any solvent; If its condition then can specifically be got rid of it outside scope of the present invention for one or more solvents in the solvent of listing more than abandoning protecting.
When SAIB was used as HVLCM, preferred solvent comprised ethanol, dimethyl sulfoxine, ethyl lactate, ethyl acetate, benzylalcohol, glyceryl triacetate, N-Methyl pyrrolidone, Allyl carbonate and Tetrahydrofurfuryl polyethylene glycol ether.SAIB not with glycerol, Semen Maydis oil, Oleum Arachidis hypogaeae semen, 1,2-propylene glycol, Polyethylene Glycol (PEG200), ultra refining Oleum sesami and ultra refining Oleum Arachidis hypogaeae semen are miscible.Therefore, preferably the one group of solvent in back is not used with SAIB.
" solvability " means the amount of one or more solvents, and it is identical with the dissolved degree of straight chain polymer with the HVLCM in the preparation with supposition amount N-Methyl pyrrolidone in the HVLCM in the preparation and the dissolved degree of straight chain polymer and the preparation.Solvability is expressed as the gross weight based on the supposition preparation that contains N-Methyl pyrrolidone, the supposition percentage by weight of N-Methyl pyrrolidone in the preparation.
Therefore, in one embodiment, solvability be about 20% preparation will have capacity one or more solvents with dissolving HVLCM and straight chain polymer, reach with the NMP that in preparation, adds about 20% weight ratio but not this one or more solvent phase with degree.If in this embodiment, NMP exists as these one or more solvents, and it will exist with the amount based on about 20% weight ratio of total formulation weight amount.If these one or more solvents are solvents poorer for HVLCM and straight chain polymer, then said one or more solvents will be to exist based on the amount of total formulation weight amount greater than about 20% weight ratio.This further specifies in embodiment 10 and 11.
In certain embodiments; When R (in the straight chain polymer lactide repetitive with all the ratio of repetitives) is about 0.55 to 0.85 the time; The solvability of one or more solvents is more than or equal to about 35%, more preferably greater than or equal about 25%, and more preferably greater than or equal about 20%.Likewise, in certain embodiments, when R is greater than 0.85 to about 0.95 the time, the solvability of one or more solvents is more than or equal to about 25%, more preferably greater than or equal about 15%, and more preferably greater than or equal about 10%.The reduction of solvability lower limit representes to require the dwindling of scope of the preparation protected.This is to reduce along with the reduction of solvability lower limit owing to number that the four corner to cited solvability shows the preparation of satisfied solubility behavior.
" individual (subject) " can exchange with " individual (individual) " and use, and means any human or animal that expectation is used for embodiment of the present invention.The concrete age do not specified in term " individuality ", so body series is suitable for the individuality at any age, for example baby, teenager, adult and older individuals.In certain embodiments, individuality can comprise the patient.
The weight average molecular weight of the interested polymer of " weight average molecular weight " or " Mw " expression.It can be expressed as the first moment of the weight of polymer in each molecular wt scope to the figure of molecular wt.In certain embodiments, gel permeation chromatography (GPC) be can pass through and weight average molecular weight, number-average molecular weight (Mn) and molecular weight distribution (MWD=Mw/Mn) measured.GPC is the post stage division, wherein based on the polymer molecule in the apart solution.Generating the GPC chromatogram, it is elution volume or time (relevant with the molecular size) figure to abundance through the isolating polymer molecule of detector observes.Can quadrature to measure Mw, Mn and MWD to the GPC chromatograph.
Sample introduction is to device, and the 10ml solvent that will contain the GPC sample of the interested polymer of 50mg of having an appointment filters through 0.2 μ m Teflon filter.Sample introduction 50-200 μ l is to generate chromatogram.Can use various systems to generate chromatogram.In one embodiment, system comprises the Agilent LC 1100 that uses Chemstation software.In another embodiment, system comprises Waters 510 pumps, Shimadzu CTO-10A column oven and Waters 410 differential refractometers.Polymer Labs data capture unit that can be through using
software directly with data record to PC.Can use polystyrene standards to generate calibration curve.Calculating is with respect to Mw, Mn and the MWD of polystyrene.The preferred solvent that is used for GPC comprises chloroform, dichloromethane (METHYLENE CHLORIDE) and oxolane (THF).Preferred different chromatographic column combination comprises: (1) placed in-line two Polymer Labs Mixed C posts, (2) placed in-line two Polymer Labs Mixed D posts, or (3) placed in-line two Polymer Labs Mesopore chromatographic columns.Preferred polystyrene calibration object comprises: Polymer Labs Easical PS1 test kit, Polymer Labs Easical PS2 test kit, Polymer Labs S-L-10 test kit.
In embodiments, the weight average molecular weight that is used for the polymer of embodiment of the present invention is less than or equal to about 15,000 dalton, is more preferably less than in addition or equals about 12,500 dalton, and be more preferably less than or equal about 10,000 dalton.
Preparation
That kind as noted above, the important consideration in the exploitation of preparation of the present invention be polymer in preparation with compatibility or the dissolubility of HVLCM.Polymer in preparation is not miscible or be insoluble under the situation of HVLCM with HVLCM, and being separated of polymer and HVLCM in the preparation can be taken place.In case this situation takes place, possibly be difficult to polymer and HVLCM remix, particularly when soon using.If remix possibly cause the variation of not expecting significantly of release performance inadequately.Therefore, the expectation polymer has height miscibility or dissolubility with HVLCM in preparation.
Preparation of the present invention has the height miscibility or the dissolubility of polymer and HVLCM in the preparation.Be used for to comprise main points as mentioned below according to other main points that the preparation strategy is considered.Make the total solvent content of preparation minimize expectation biology normally; For example in one embodiment; Solvent is that about 1wt% is extremely up to about 35wt% solvent based on the gross weight of preparation; The gross weight that is preferably based on preparation for about 1wt% to up to about 30wt% solvent, and be that about 1wt% is extremely up to about 25wt% solvent more preferably based on the gross weight of preparation.By contrast, increasing solvent can move from being separated HVLCM/ straight chain polymer compositions to single-phase behavior.One or more solvents should be biocompatible, and it can get rid of the use in the present invention of some solvent.In one embodiment, one or more solvents should be to polymer and the good solvent of HVLCM both.In optional embodiment, preparation can comprise HVLCM, straight chain polymer, one or more solvent and one or more to HVLCM good solvents good to straight chain polymer, and the gained preparation is monophasic.
The vision technique that can know is by one of skill in the art studied the dissolubility of various HVLVM/ straight chain polymer/solvent formulation and is separated.For obvious instability or the preparation that tends to be separated, straight chain polymer can lyosoption but still as isolating, very sticking layer or be retained in the preparation mutually.Can make other preparation become uniform settled solution through abundant heating and mixing.Yet, when being cooled to room temperature, can form two kinds of clarifying liquid phases.Sometimes, be not easy to detect these two kinds clarifying layers, therefore need high light and to the end-to-end of preparation to differentiate two alternate borders.In many cases, preparation can when initially being cooled to room temperature, show as clarification with evenly, but at room temperature left standstill several days or after longer time, said preparation can be divided into biphase.For at the preparation at edge that is separated, preparation can become muddy and sometimes be divided into biphase lentamente.
Preparation of the present invention can randomly comprise various additives to improve the expectation attribute of preparation.Additive can exist with any amount that is enough to give preparation expectation attribute.The amount of additive therefor generally is the function of additive character and the effect that will obtain, and those skilled in the art can easily confirm.
When having additive, additive is usually being present in the preparation with respect to total formulation weight amount about 0.1% amount to about 20% weight ratio, and more generally to be present in the compositions with respect to about 1%, 2% or 5% amount to about 10% weight ratio of total formulation weight amount.Some additive such as buffer agent can be only with existing with respect to the total formulation weight amount on a small quantity.
The another kind of additive that the present composition uses is non-Biodegradable polymeric.The limiting examples of the polymer of the difficult erosion that can use as additive comprise polyacrylate, ethane-acetic acid ethyenyl ester polymer, cellulose and cellulose derivative, acyl substituted cellulose acetate and derivant thereof, be difficult for erosion polyurethanes, polystyrene, polrvinyl chloride, polyvinyl fluoride, gather (vinyl imidazole), chlorosulfonated polyolefin and PEO.
Preferred nonbiodegradable polymer comprises polyethylene, polyvinylpyrrolidone, ethylene vinyl acetate, Polyethylene Glycol, cellulose acetate-butyrate (" CAB ") and cellulose-acetate propionate (" CAP ").
The another kind of additive that can be used for preparation of the present invention is natural and synthetic oil & fat.From animal or to generally include from the oil of plant nut-seed mainly be the glyceride of oleic acid, Palmic acid, stearic acid and linolenic fatty acid.Usually, the hydrogen that molecule contains is many more, and it is thick more that oil becomes.
The limiting examples of suitable natural and synthetic oil comprises rough or refined vegetable oils, Oleum Arachidis hypogaeae semen, medium chain triglyceride, Oleum Glycines, almond oil, olive oil, Oleum sesami, Oleum Arachidis hypogaeae semen, Oleum Anisi Stellati, Camellia oil, Semen Maydis oil, Oleum Ricini, Oleum Gossypii semen and Oleum Glycines, and MCT Oil.
Fat is normally such as the glyceride of the higher fatty acids of stearic acid and Palmic acid.These esters and composition thereof at room temperature are solids and show crystal structure.Adeps Sus domestica and Adeps Bovis seu Bubali are instances.Usually, oil & fat has increased the hydrophobicity of preparation and has delayed the absorption of degraded and water.
The another kind of additive that can be used for preparation of the present invention comprises carbohydrate and carbohydrate derivates.The limiting examples of these chemical compounds comprises monosaccharide (such as the simple sugars of fructose and isomer glucose (dextrose) thereof), such as the disaccharide and the polysaccharide of sucrose, maltose, cellobiose and lactose.
Can add other additive on demand, for example antiseptic, stabilizing agent, antioxidant, coloring agent, isotonic agent, wetting agent, chelating agent, vitamin and previtamin, surfactant etc.The preferred embodiment of antiseptic is p-Hydroxybenzoate (paraben) derivant, and methyl parahydroxybenzoate and propyl p-hydroxybenzoate are most preferred antiseptic.The preferred embodiment of antioxidant is the hydroquinone of Butylated hydroxyanisole, butylated hydroxytolyene, propyl gallate, vitamin E acetate and purification, and vitamin E acetate and butylated hydroxytolyene are most preferred antioxidants.The preferred embodiment of wetting agent is a sorbitol.The preferred embodiment of chelating agent is a citric acid.
Can be according to the preparation of many method preparation inventions.In certain embodiments, at first with the solvent under the room temperature, the straight chain polymer under the room temperature and the HVLCM mixing that is heated to 80 ℃.Then, in the time of 60-80 ℃ of following mixed number hour to spend the night (8-16 hour), fully mix until preparation.In other embodiments, straight chain polymer is dissolved in all solvents.Add hot HVLCM (in heating down) up to 80 ℃.Then, under the temperature of room temperature to 80 ℃, mix and reach 1 hour time, fully mix until preparation to spend the night (8-16 hour).In other embodiments, straight chain polymer is dissolved in some solvent in the solvent.Remaining solvent is mixed with HVLCM.In straight chain polymer/solvent mixture, add hot HVLCM/ solvent mixture (in heating down) up to 80 ℃.Under the temperature of room temperature to 80 ℃, mix then and reach 1 hour, fully mix until preparation to spend the night (8-16 hour).
Preferably be higher than preparation preparation of the present invention under the temperature of room temperature.In case mix, can preparation cooled back room temperature and observe the existence of muddy (the isolating sign of preliminary phase), two liquid levels (have usually and be low to moderate medium viscosity) or in the existence than the viscous layer below the low-viscous layer for the first time.Can preparation be placed room temperature to reach the suitable time (be generally one week or longer) and observes existence muddy, that be divided into the two-layer or viscous layer of moderate tack once more then.
Can use conventional route of administration to give individual preparation of the present invention such as injection.Thereby can add the pharmacological effect of the bioactive substance acquisition expectation of effective dose to preparation of the present invention.
Though described and pointed out characteristic of the present invention and advantage; As be applied to this embodiment; The technical staff of medical field will understand, and can carry out various modifications, variation, increase and abreviation and not depart from spirit of the present invention the described method of this description.
The present invention does not receive the restriction according to the described specific embodiments of the application, and this specific embodiments is intended to the independent example as various aspects of the present invention.It will be apparent to one skilled in the art that and can carry out many modifications and change the present invention, and without departing from the spirit and scope of the present invention.Except this paper enumerates those, suitable method it will be apparent to those skilled in the art that on the function in the scope of the invention of aforementioned description.These modifications and change are intended to fall in the scope of appending claims.The present invention only receives the restriction of whole equivalency range of appending claims and these granted entitlements claims.
The intention of following embodiment is an example, and the invention of requirement for restriction protection never in any form.
Embodiment
Embodiment 1: FORMULATION EXAMPLE
Prepared according to various FORMULATION EXAMPLE of the present invention, and various control formulation embodiment.The information relevant with these embodiment is as shown in table 1.Hereinafter has been listed the synthetic and preparation technique of polymer of some exemplary embodiment.The remaining non-exemplary embodiment of modification preparation of using these representational technology and these representative art conventionally to obtain.
Embodiment 2:
Three mouthfuls of round-bottomed flasks of dry 500mL, glassed agitator bearing, gas connection and glass shaft are to remove all traces of moisture in 100 ℃ glass drying oven baking oven.In flask, add following material: 179.00g DL-lactide, 71.00g Acetic acid, hydroxy-, bimol. cyclic ester and 13.75g 1,6-hexanediol.Flask is equipped with shaft with Teflon slurry, agitator bearing and the gas connection that links to each other with nitrogen supply (NS) with vacuum manifold.With rubber balloon sealed stirrer axle/bearing, the reactant mixture of finding time reaches a few minutes also with nitrogen backfill flask.The overhead type agitator that the flask immersion remains in the oil bath under 150 ℃ and use links to each other with axle/oar assembly is stirred.In case all monomers all melt, in melt, add the toluene solution (concentration is the 559mL solution of 0.13416g/mL) that contains the 0.075g stannous 2-ethylhexoate.Continue to stir 4 hours.Then oil bath temperature is reduced to 115 ℃, stop to stir and, and reactant mixture was found time in the perfect vacuum 1 hour with rubber balloon sealed stirrer axle/bearing.Then polymer is poured on the Teflon thin film in the glass saucer and with its cooling.The polymer of accomplishing is stored in vacuum drying oven and/or the plastic bag with isolation environment moisture.The polymer of gained is about 5300Da through the Mw that GPC measures, and the R ratio is 0.65.
Embodiment 3: preparation 6
From cryopreservation, take out PLGA polymer, and it is warming up to room temperature according to embodiment 2 preparations.SAIB (in glass jar) is heated to 80 ℃, continues several hours.Hot SAIB pours in the glass jar with 5.69 grams.Then 2.59 gram NMP are added in this glass jar.Then, 2.05 gram 65/35PLGA polymer are added in this glass jar.This wide mouthed bottle is sealed and is fixed to rotation mixed wheel (rotating mixing wheel).This mixed wheel is put into 80 ℃ baking oven and is opened, thus make this wide mouthed bottle in the outside of circular path to be enough to realize that blended speed rotates.After mixing 2 hours under 80 ℃, from mixed wheel, take out this wide mouthed bottle and it is cooled to room temperature.Preparation consists of 55%SAIB, 25%NMP and 20%PLGA.During placement, preparation keeps clarification and does not show any sign that is separated.
Embodiment 4:
Three mouthfuls of round-bottomed flasks of dry 1L, glassed agitator bearing, gas connection and shaft are to remove all traces of moisture in 100 ℃ glass drying oven baking oven.In flask, add following material: 179.00g DL-lactide, 71.00g Acetic acid, hydroxy-, bimol. cyclic ester and 2.1g water.Flask is equipped with shaft, Teflon slurry, agitator bearing and the gas connection that links to each other with nitrogen supply (NS) with vacuum manifold.Sealed stirrer axle/bearing, the reactant mixture number minute and of finding time with nitrogen backfill flask.This process is repeated 4 times again.The overhead type agitator that the flask immersion remains in the oil bath under 159 ℃ and use links to each other with axle/oar assembly is stirred.In case all monomers all melt, add the toluene solution that contains the 0.1125g stannous 2-ethylhexoate to melt.Continue to stir 15 hours.Then oil bath temperature is reduced to 115 ℃, stop to stir and sealed stirrer axle/bearing, and reactant mixture was found time in the perfect vacuum 1 hour.Then polymer is poured on the Teflon thin film in the glass saucer and with its cooling.The polymer of accomplishing is kept in vacuum drying oven and/or the plastic bag with isolation environment moisture.Resulting polymers is about 7200Da through the Mw that GPC measures, and the R ratio is 0.65.
Embodiment 5: control formulation C3
To be dissolved in 1.55 gram DMSO and the alcoholic acid mixture of 1.55 grams according to 3.28 gram PLGA of embodiment 4 preparations.Add the hot SAIB of 24.98 grams, the topic that obtains containing 10.5%PLGA, 4.9%DMSO, 4.9% ethanol and 79.7%SAIB is stated preparation.Said preparation at room temperature is divided into biphase.Add other DMSO (3.90 gram) and other ethanol (2.25 restrain) and state preparation with the topic that obtains containing 8.8%PLGA, 14.5%DMSO, 10.1% ethanol and 66.6%SAIB.Said preparation keeps being divided into two-layer.
Embodiment 6: preparation 6 (optional formulation method is learned)
From cryopreservation, take out PLGA polymer, and it is warming up to room temperature according to embodiment 2 preparations.20.36 gram 65/35PLGA polymer are added in the glass jar.In this wide mouthed bottle, add 25.45 gram NMP, and with this wide mouthed bottle sealing.With this wide mouthed bottle be fixed to the rotation mixed wheel (Glas CoI, Terre Haute, IN).Thereby open this mixed wheel and make the external rotating of this wide mouthed bottle, and heating is dissolved among the NMP until polymer under about 80 ℃ at circular path.In polymer/nmp solution, add 55.49 gram SAIB (heating).Seal this wide mouthed bottle and secure it to the rotation mixed wheel (Glas CoI, Terre Haute, IN).Thereby open mixed wheel make this wide mouthed bottle in the outside of circular path to be enough to realize that blended speed rotates.Mixed solution is until realizing preparation uniformly.Preparation consists of 55%SAIB, 25%NMP and 20%PLGA, and all percentage ratios all are expressed as the wt% based on the total formulation weight amount.During placement, this medium keeps clarification and does not show any sign that is separated.
Embodiment 7: the solvability test
With molecular weight is that 4700Da, lactide/glycolides ratio are 65/35 and are added into (weight relationships that is polymer and SAIB is fixed) in the bottle with about 2.5g PLGA and 6.855g SAIB that hexanediol causes.Slowly add shown in hereinafter table 2 solvent and under 60 ℃ in Emprotech
baking oven mix preparation, until forming single phase soln.From baking oven, take out this solution then, and it is placed about 1 week on the laboratory table under about room temperature.If solution is separated, then add more solvent and at 60 ℃ of following mix preparations until forming monophasic solution, and it places under about room temperature and still keeps single-phase on the laboratory table 1 week.Final composition is shown in the table of hereinafter table 2.The solvability of this medium is 25.61wt%.The DMSO of BA or 42.64wt% that needs 26.44wt% is to realize this solvability.
Table 2 (numeral is the percentage by weight of total final weight)
| Material | Test A | Test B | Test C |
| SAIB | 53.86 | 41.99 | 54.55 |
| PLGA | 19.70 | 15.37 | 19.84 |
| NMP | 25.61 | ||
| BA | 26.44 | ||
| DMSO | 42.64 |
Embodiment 8: the solvability test
With molecular weight is that 6600Da, lactide/glycolides ratio are 65/35 and are added in the bottle with about 2.5g PLGA and 6.855g SAIB that dodecanol causes.Slowly add shown in hereinafter table 3 solvent and under 60 ℃ in Emprotech
baking oven mix preparation, until forming single phase soln.From baking oven, take out this solution then, and it is placed about 1 week on the laboratory table under about room temperature.If solution is separated, then add more solvent and at 60 ℃ of following mix preparations until forming monophasic solution, and it places on the laboratory table 1 still to keep single-phase when all under about room temperature.Be shown in the hereinafter table 3 final the composition.The solvability of this medium is 17.36wt%.The DMSO of BA or 31.22wt% that needs 19.70wt% is to realize this solvability.
Table 3 (numeral is the percentage by weight of total final weight)
| Material | Test D | Test E | Test F |
| SAIB | 58.83 | 50.37 | 60.58 |
| PLGA | 21.47 | 18.41 | 22.06 |
| NMP | 17.36 | ||
| BA | 19.70 | ||
| DMSO | 31.22 |
Embodiment 9: the naltrexone preparation
In 60 ℃ Lindberg/Blue M baking oven; Through in air-tight bottle, reversing gently 35 minutes; With 0.555 gram PLGA (65/35L/G; Cause with the 1-dodecanol; The MW that records through GPC is 6400 dalton, from
Birmingham) mix with 3.620 gram benzylalcohols (from J.T.Baker), obtain the solution of homogenizing.In this mixture, add 6.094 gram hot SAIB (from Eastman Chemicals).Through at room temperature reversing about 65 hours blending agents gently.Obtained uniform medium (SAIB/ benzylalcohol/PLGA 59.34/35.25/5.40).In another bottle, add 0.118 gram naltrexone alkali (Mallinckrodt).In this bottle, add 4.205 these media of gram.Through reversing gently about 3 hours, naltrexone is dissolved in this medium, obtain evenly, clarification, lurid solution.The composition of naltrexone preparation (wt% with based on whole weight of formulation representes) is:
PLGA： 5.3％
Benzylalcohol 34.3%
SAIB 57.7％
Naltrexone 2.7%
Embodiment 10: the Risperidone preparation
The atypical antipsychotic agents Risperidone is added into as follows in the preparation (preparation 26) of embodiment 3:
Restrain interpolation 1.095 gram Risperidones (from Kemprotec) in the agent 26 to 7.33.Bottle placed be made as on 30% the Glas-Col swiveling wheel about 2 hours, until the suspension that obtains homogenizing.The gained preparation consist of 48%SAIB, 22%NMP, 17%PLGA and 13% Risperidone, all percentage ratios all are expressed as the percentage by weight based on the total formulation weight amount.The gained medium is stable homogeneous suspension.
Table 1:
Claims (6)
1. preparation, it comprises:
(i) Sucrose acetoisobutyrate (SAIB);
(ii) straight chain lactide-glycolide copolymer, wherein:
The ratio of whole repetitives is R in-lactide repetitive and the said straight chain lactide-glycolide copolymer, and said R satisfies following condition: 0.55≤R≤0.85;
The weight average molecular weight of-said straight chain lactide-glycolide copolymer is less than or equal to 15,000 dalton; And
-based on said total formulation weight amount, the amount of said straight chain lactide-glycolide copolymer is 15wt% to 45wt%; And
(iii) N-Methyl pyrrolidone, wherein based on said total formulation weight amount, the amount of N-Methyl pyrrolidone is greater than 20wt%.
2. preparation as claimed in claim 1, the amount of wherein said N-Methyl pyrrolidone is more than or equal to 25wt%.
3. preparation as claimed in claim 2, the amount of wherein said N-Methyl pyrrolidone is more than or equal to 35wt%.
4. preparation as claimed in claim 1, it also comprises bioactive substance.
5. preparation as claimed in claim 4, wherein said bioactive substance comprises atypical antipsychotic agents.
6. preparation as claimed in claim 5, wherein said atypical antipsychotic agents comprise Risperidone or acceptable salt of its medicine or polymorph.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US93073907P | 2007-05-18 | 2007-05-18 | |
| US60/930,739 | 2007-05-18 | ||
| PCT/US2008/006320 WO2008143992A2 (en) | 2007-05-18 | 2008-05-16 | Improved depot formulations |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210392622.4A Division CN103007288B (en) | 2007-05-18 | 2008-05-16 | Improved depot formulations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101677952A CN101677952A (en) | 2010-03-24 |
| CN101677952B true CN101677952B (en) | 2012-12-05 |
Family
ID=39708928
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008800208290A Expired - Fee Related CN101677952B (en) | 2007-05-18 | 2008-05-16 | Improved depot formulations |
| CN201210392622.4A Expired - Fee Related CN103007288B (en) | 2007-05-18 | 2008-05-16 | Improved depot formulations |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210392622.4A Expired - Fee Related CN103007288B (en) | 2007-05-18 | 2008-05-16 | Improved depot formulations |
Country Status (12)
| Country | Link |
|---|---|
| US (8) | US20080287464A1 (en) |
| EP (2) | EP2167039B1 (en) |
| JP (4) | JP5599705B2 (en) |
| CN (2) | CN101677952B (en) |
| AU (1) | AU2008254538B2 (en) |
| CA (1) | CA2686137C (en) |
| DK (1) | DK2167039T3 (en) |
| ES (1) | ES2606951T3 (en) |
| HU (1) | HUE030789T2 (en) |
| IL (1) | IL202181A (en) |
| PL (1) | PL2167039T3 (en) |
| WO (1) | WO2008143992A2 (en) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070027105A1 (en) | 2005-07-26 | 2007-02-01 | Alza Corporation | Peroxide removal from drug delivery vehicle |
| US8852638B2 (en) | 2005-09-30 | 2014-10-07 | Durect Corporation | Sustained release small molecule drug formulation |
| KR20100016142A (en) * | 2007-04-03 | 2010-02-12 | 트라이머리스, 인코퍼레이티드 | Novel formulations for delivery of antiviral peptide therapeutics |
| CN101677952B (en) | 2007-05-18 | 2012-12-05 | 杜雷科特公司 | Improved depot formulations |
| EP2907524A1 (en) | 2007-05-25 | 2015-08-19 | RB Pharmaceuticals Limited | Sustained delivery formulations of risperidone compounds |
| US8524267B2 (en) * | 2008-04-18 | 2013-09-03 | Warsaw Orthopedic, Inc. | Dexamethasone formulations in a biodegradable material |
| US10335366B2 (en) | 2010-05-31 | 2019-07-02 | Laboratorios Farmacéuticos Rovi, S.A. | Risperidone or paliperidone implant formulation |
| US10285936B2 (en) | 2010-05-31 | 2019-05-14 | Laboratorios Farmacéuticos Rovi, S.A. | Injectable composition with aromatase inhibitor |
| EP2394664B1 (en) * | 2010-05-31 | 2016-06-01 | Laboratorios Farmaceuticos Rovi, S.A. | Antipsychotic injectable depot composition |
| US10350159B2 (en) | 2010-05-31 | 2019-07-16 | Laboratories Farmacéuticos Rovi, S.A. | Paliperidone implant formulation |
| US10463607B2 (en) | 2010-05-31 | 2019-11-05 | Laboratorios Farmaceutics Rofi S.A. | Antipsychotic Injectable Depot Composition |
| US10881605B2 (en) | 2010-05-31 | 2021-01-05 | Laboratorios Farmaceuticos Rovi, S.A. | Methods for the preparation of injectable depot compositions |
| SMT202100679T1 (en) | 2010-05-31 | 2022-01-10 | Laboratorios Farmaceuticos Rovi S A | Compositions for injectable in-situ biodegradable implants |
| AU2011336896B2 (en) * | 2010-11-24 | 2015-12-24 | Durect Corporation | Biodegradable drug delivery composition |
| SI2529756T1 (en) * | 2011-05-31 | 2021-09-30 | Laboratorios Farmaceuticos Rovi, S.A. | Risperidone and/or Paliperidone implant formulation |
| US20140294977A1 (en) | 2011-11-23 | 2014-10-02 | Durect Corporation | Radiation-Sterilized Biodegradable Drug Delivery Composition |
| CN115804749A (en) * | 2013-03-11 | 2023-03-17 | 度瑞公司 | Injectable controlled release compositions comprising high viscosity liquid carriers |
| US20140308352A1 (en) | 2013-03-11 | 2014-10-16 | Zogenix Inc. | Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material |
| JP6564369B2 (en) | 2013-12-09 | 2019-08-21 | デュレクト コーポレイション | Pharmaceutically active agent conjugates, polymer conjugates, and compositions and methods involving them |
| US11090296B2 (en) | 2015-03-18 | 2021-08-17 | Santen Pharmaceutical Co., Ltd. | Sustained-release pharmaceutical composition |
| CA2972296A1 (en) | 2016-06-30 | 2017-12-30 | Durect Corporation | Depot formulations |
| US10682340B2 (en) | 2016-06-30 | 2020-06-16 | Durect Corporation | Depot formulations |
| CA3146064A1 (en) * | 2019-07-18 | 2021-01-21 | Durect Corporation | Long-acting formulations and vehicles |
| US20220257619A1 (en) * | 2019-07-18 | 2022-08-18 | Gilead Sciences, Inc. | Long-acting formulations of tenofovir alafenamide |
| JP2023515918A (en) | 2020-01-13 | 2023-04-17 | デュレクト コーポレーション | Sustained release drug delivery system with reduced impurities and related methods |
| TW202313047A (en) | 2021-09-21 | 2023-04-01 | 西班牙商禾霏藥品實驗室有限公司 | Antipsychotic injectable depot composition |
| AU2023281232A1 (en) | 2022-05-18 | 2024-10-24 | Laboratorios Farmacéuticos Rovi, S.A. | Prolonged-release injectable compositions for use in treatment with risperidone together with cyp2d6 enzyme inhibitors |
| CN117815172A (en) * | 2024-01-08 | 2024-04-05 | 江苏诺和必拓新药研发有限公司 | Meloxicam sustained-release injection, preparation method thereof and medicine for relieving pain of arthritis |
Family Cites Families (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE52535B1 (en) * | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
| US4530840A (en) | 1982-07-29 | 1985-07-23 | The Stolle Research And Development Corporation | Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents |
| US4906474A (en) * | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
| US4622219A (en) | 1983-06-17 | 1986-11-11 | Haynes Duncan H | Method of inducing local anesthesia using microdroplets of a general anesthetic |
| US4725442A (en) | 1983-06-17 | 1988-02-16 | Haynes Duncan H | Microdroplets of water-insoluble drugs and injectable formulations containing same |
| US4891225A (en) | 1984-05-21 | 1990-01-02 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
| IT1198449B (en) | 1986-10-13 | 1988-12-21 | F I D I Farmaceutici Italiani | ESTERS OF POLYVALENT ALCOHOLS OF HYALURONIC ACID |
| US4938763B1 (en) * | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
| US5149543A (en) * | 1990-10-05 | 1992-09-22 | Massachusetts Institute Of Technology | Ionically cross-linked polymeric microcapsules |
| EP0566744B1 (en) * | 1991-10-22 | 2000-01-05 | KOIKE, Yasuhiro | Refractive index distribution type optical fibre and method of manufacturing said optical fibre |
| NZ260909A (en) * | 1993-07-05 | 1995-04-27 | Takeda Chemical Industries Ltd | Production of sustained release preparation by allowing a water-soluble polypeptide to permeate into a biodegradable matrix in an aqueous solution |
| US5643605A (en) * | 1993-10-25 | 1997-07-01 | Genentech, Inc. | Methods and compositions for microencapsulation of adjuvants |
| AU684324B2 (en) | 1993-11-19 | 1997-12-11 | Alkermes Controlled Therapeutics Inc. Ii | Preparation of biodegradable microparticles containing a biologically active agent |
| US5747058A (en) * | 1995-06-07 | 1998-05-05 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system |
| US7833543B2 (en) | 1995-06-07 | 2010-11-16 | Durect Corporation | High viscosity liquid controlled delivery system and medical or surgical device |
| US5968542A (en) * | 1995-06-07 | 1999-10-19 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system as a device |
| US6413536B1 (en) * | 1995-06-07 | 2002-07-02 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system and medical or surgical device |
| DE69737515T2 (en) | 1996-05-07 | 2007-12-06 | Alkermes, Inc., Cambridge | Micro particles |
| CA2275525C (en) * | 1996-12-20 | 2011-02-08 | Kevin J. Brodbeck | Gel composition and methods |
| ES2359973T3 (en) * | 1998-03-19 | 2011-05-30 | MERCK SHARP & DOHME CORP. | LIQUID POLYMER COMPOSITIONS FOR THE CONTROLLED RELEASE OF BIOACTIVE SUBSTANCES. |
| US7208011B2 (en) * | 2001-08-20 | 2007-04-24 | Conor Medsystems, Inc. | Implantable medical device with drug filled holes |
| US6143314A (en) | 1998-10-28 | 2000-11-07 | Atrix Laboratories, Inc. | Controlled release liquid delivery compositions with low initial drug burst |
| US6291013B1 (en) * | 1999-05-03 | 2001-09-18 | Southern Biosystems, Inc. | Emulsion-based processes for making microparticles |
| WO2002000137A1 (en) | 2000-06-28 | 2002-01-03 | Shukla Atul J | Biodegradable vehicles and delivery systems of biologically active substances |
| EP1335704A2 (en) * | 2000-11-16 | 2003-08-20 | Durect Corporation | Implant dosage form and use thereof for the delivery of a cholesterol lowering agent |
| US20040018238A1 (en) * | 2001-02-26 | 2004-01-29 | Shukla Atul J | Biodegradable vehicles and delivery systems of biolgically active substances |
| EP1379197A4 (en) * | 2001-03-23 | 2009-06-03 | Durect Corp | Delivery of drugs from sustained release devices implanted in myocardial tissue or in the pericardial space |
| GB0112324D0 (en) * | 2001-05-21 | 2001-07-11 | Croda Int Plc | Compounds |
| KR20040058101A (en) | 2001-11-14 | 2004-07-03 | 알자 코포레이션 | Catheter injectable depot compositions and uses thereof |
| MXPA04004663A (en) | 2001-11-14 | 2004-09-10 | Alza Corp | Injectable depot compositions and uses thereof. |
| CA2466642C (en) | 2001-11-14 | 2011-01-18 | Guohua Chen | Injectable depot composition |
| US20040258731A1 (en) | 2001-11-21 | 2004-12-23 | Tsuyoshi Shimoboji | Preparation approriate for cartilage tissue formation |
| TWI314464B (en) | 2002-06-24 | 2009-09-11 | Alza Corp | Reusable, spring driven autoinjector |
| TWI353854B (en) | 2002-06-25 | 2011-12-11 | Alza Corp | Short duration depot formulations |
| US20040109893A1 (en) * | 2002-06-25 | 2004-06-10 | Guohua Chen | Sustained release dosage forms of anesthetics for pain management |
| US7097634B2 (en) | 2002-07-31 | 2006-08-29 | Alza Corporation | Injection device providing automatic needle retraction |
| KR20050083605A (en) | 2002-07-31 | 2005-08-26 | 알자 코포레이션 | Injectable multimodal polymer depot compositions and uses thereof |
| JP2006508127A (en) | 2002-11-06 | 2006-03-09 | アルザ・コーポレーション | Controlled release depot formulation |
| US7005225B2 (en) * | 2002-11-12 | 2006-02-28 | Samsung Electronics Company | Organosol including amphipathic copolymeric binder having crystalline material, and use of the organosol to make dry tones for electrographic applications |
| EP2959893A1 (en) | 2002-12-13 | 2015-12-30 | DURECT Corporation | Oral drug delivery system comprising high viscosity liquid carrier materials |
| DE10312346A1 (en) * | 2003-03-20 | 2004-09-30 | Bayer Healthcare Ag | Controlled release system |
| JP2007504256A (en) | 2003-09-01 | 2007-03-01 | メイン・ファ−マ・インタ−ナショナル・プロプライエタリ−・リミテッド | Compositions and methods for delivery of bioactive agents |
| US20050281879A1 (en) | 2003-11-14 | 2005-12-22 | Guohua Chen | Excipients in drug delivery vehicles |
| MY158342A (en) * | 2003-11-14 | 2016-09-30 | Novartis Ag | Pharmaceutical composition |
| US20100016267A1 (en) * | 2004-03-15 | 2010-01-21 | Felix Theeuwes | Pharmaceutical compositions for administraton to a sinus |
| US20050240166A1 (en) * | 2004-04-26 | 2005-10-27 | Microsolutions, Inc. | Implantable device, formulation and method for anti-psychotic therapy using risperidone |
| GB0412866D0 (en) * | 2004-06-09 | 2004-07-14 | Novartis Ag | Organic compounds |
| US8852638B2 (en) * | 2005-09-30 | 2014-10-07 | Durect Corporation | Sustained release small molecule drug formulation |
| CN101400363B (en) | 2006-01-18 | 2012-08-29 | 昌达生物科技公司 | Pharmaceutical compositions with enhanced stability |
| CN101677952B (en) * | 2007-05-18 | 2012-12-05 | 杜雷科特公司 | Improved depot formulations |
| WO2009100222A1 (en) | 2008-02-08 | 2009-08-13 | Qps Llc | Non-polymeric compositions for controlled drug delivery |
| US20140308352A1 (en) | 2013-03-11 | 2014-10-16 | Zogenix Inc. | Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material |
-
2008
- 2008-05-16 CN CN2008800208290A patent/CN101677952B/en not_active Expired - Fee Related
- 2008-05-16 JP JP2010508444A patent/JP5599705B2/en not_active Expired - Fee Related
- 2008-05-16 ES ES08767765.4T patent/ES2606951T3/en active Active
- 2008-05-16 DK DK08767765.4T patent/DK2167039T3/en active
- 2008-05-16 WO PCT/US2008/006320 patent/WO2008143992A2/en active Application Filing
- 2008-05-16 HU HUE08767765A patent/HUE030789T2/en unknown
- 2008-05-16 CN CN201210392622.4A patent/CN103007288B/en not_active Expired - Fee Related
- 2008-05-16 EP EP08767765.4A patent/EP2167039B1/en not_active Not-in-force
- 2008-05-16 AU AU2008254538A patent/AU2008254538B2/en not_active Ceased
- 2008-05-16 EP EP16182848.8A patent/EP3115038A1/en not_active Withdrawn
- 2008-05-16 CA CA2686137A patent/CA2686137C/en active Active
- 2008-05-16 US US12/152,764 patent/US20080287464A1/en not_active Abandoned
- 2008-05-16 PL PL08767765T patent/PL2167039T3/en unknown
-
2009
- 2009-11-17 IL IL202181A patent/IL202181A/en active IP Right Grant
-
2013
- 2013-03-08 US US13/790,902 patent/US10028957B2/en active Active
-
2014
- 2014-05-07 JP JP2014095775A patent/JP6018603B2/en not_active Expired - Fee Related
-
2015
- 2015-07-16 US US14/801,141 patent/US20160045601A1/en not_active Abandoned
-
2016
- 2016-02-26 US US15/054,473 patent/US20160279131A1/en not_active Abandoned
- 2016-07-29 JP JP2016149343A patent/JP6339640B2/en not_active Expired - Fee Related
-
2018
- 2018-05-10 JP JP2018091049A patent/JP2018158921A/en active Pending
- 2018-06-25 US US16/017,477 patent/US20190030032A1/en not_active Abandoned
-
2019
- 2019-09-03 US US16/559,155 patent/US20200101073A1/en not_active Abandoned
-
2020
- 2020-10-05 US US17/063,095 patent/US20210121467A1/en not_active Abandoned
-
2023
- 2023-01-04 US US18/093,240 patent/US20230146925A1/en not_active Abandoned
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101677952B (en) | 2012-12-05 | Improved depot formulations |
| US7053209B1 (en) | 2006-05-30 | High viscosity liquid controlled delivery system and medical or surgical device |
| US20130345260A1 (en) | 2013-12-26 | High Viscosity Liquid Controlled Delivery System and Medical or Surgical Device |
| CN1299290A (en) | 2001-06-13 | High viscosity liquid controlled delivery system as a Device |
| AU2013202476B2 (en) | 2016-04-21 | Improved depot formulations |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 2010-03-24 | C06 | Publication | |
| 2010-03-24 | PB01 | Publication | |
| 2010-07-14 | C10 | Entry into substantive examination | |
| 2010-07-14 | SE01 | Entry into force of request for substantive examination | |
| 2012-12-05 | C14 | Grant of patent or utility model | |
| 2012-12-05 | GR01 | Patent grant | |
| 2021-04-27 | CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20121205 Termination date: 20200516 |
| 2021-04-27 | CF01 | Termination of patent right due to non-payment of annual fee |